Validation of Heart Failure Events in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Participants Assigned to Doxazosin and Chlorthalidone

BACKGROUND: The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, double-blind, active-controlled trial designed to compare the rate of coronary heart disease events in high-risk hypertensive participants initially randomized to a diuretic (chlorthalidone) versus each of three alternative antihypertensive drugs: alpha-adrenergic blocker (doxazosin), ACE-inhibitor (lisinopril), and calcium-channel blocker (amlodipine). Combined cardiovascular disease risk was significantly increased in the doxazosin arm compared to the chlorthalidone arm (RR 1.25; 95% CI, 1.17-1.33; P <.001), with a doubling of heart failure (fatal, hospitalized, or non-hospitalized but treated) (RR 2.04; 95% CI, 1.79-2.32; P <.001). Questions about heart failure diagnostic criteria led to steps to validate these events further. METHODS AND RESULTS: Baseline characteristics (age, race, sex, blood pressure) did not differ significantly between treatment groups (P <.05) for participants with heart failure events. Post-event pharmacologic management was similar in both groups and generally conformed to accepted heart failure therapy. Central review of a small sample of cases showed high adherence to ALLHAT heart failure criteria. Of 105 participants with quantitative ejection fraction measurements provided, (67% by echocardiogram, 31% by catheterization), 29/46 (63%) from the chlorthalidone group and 41/59 (70%) from the doxazosin group were at or below 40%. Two-year heart failure case-fatalities (22% and 19% in the doxazosin and chlorthalidone groups, respectively) were as expected and did not differ significantly (RR 0.96; 95% CI, 0.67-1.38; P = 0.83). CONCLUSION: Results of the validation process supported findings of increased heart failure in the ALLHAT doxazosin treatment arm compared to the chlorthalidone treatment arm.     

Glandular-haired alfalfa resistance to potato leafhopper (Homoptera: Cicadellidae) and hopperburn: development of resistance indices

Eight proprietary genotypes of glandular-haired alfalfa, Medicago sativa L., supplied by two different companies, were compared for the degree and types of resistance to the potato leafhopper, Ernpoasca fabae (Harris), and hopperburn. A tube cage no-choice bioassay was developed to test leafhopper mortality, feeding, settling preferences, severity of hopperburn symptoms (in this case, defined as both yellowing and stem growth reduction), and trichome density and type on feeding sites. Leafhopper mortality was both strongly and significantly associated with feeding and leaf trichome density; decreased hopperburn symptom severity was weakly, although significantly, associated with increased mortality. To quantify hopperburn in terms of both yellowing and stem growth reduction, we developed a ranking system that reduces overall hopperburn expression to a single number that considers the varying responses to both types of symptoms. Great variability in leafhopper settling, leafhopper mortality, and stem glandular trichome density was detected among alfalfa genotypes, suggesting that genotypic differences may be based on the concentration and/or chemical constituency of the trichome exudates. We postulate that, among variably resistant genotypes of glandular-haired alfalfa, differences among leafhopper responses and hopperburn severity are linked to forced movement from the stems to the leaves as refuge feeding sites. Principal component analysis was performed to reduce the 10 variables down to five biologically significant factors. Scores for these factors were then used to develop resistance indices for potato leafhopper resistance, hopperburn resistance, and an overall glandular-haired alfalfa resistance index.     

Comparison of AC electronic monitoring and field data for estimating tolerance to Empoasca kraemeri (Homoptera: Cicadellidae) in common bean genotypes

Two methods for estimating the tolerance of common bean genotypes to Empoasca kraemeri Ross & Moore were compared, using a yield trial carried out at Centro Internacional de Agricultura Tropical (CIAT), Cali, Colombia, versus stylet penetration tactics measured by AC electronic feeding monitors. A stylet penetration index was devised based on principal component scores of three penetration tactics identified (pulsing laceration, cell rupturing, and lancing sap ingestion), combined with knowledge of the hopperburn symptoms caused by each tactic. Tolerant genotypes, as classified by the CIAT yield index, showed significantly more unprotected yield and lower hopperburn scores than the susceptible control. They also induced performance of less pulsing laceration (the tactic considered most damaging to the plant), and more of the other two, mitigating tactics, especially cell rupturing. When index values were calculated for each genotype, stylet penetration index values matched those of the yield index for three out of five genotypes: two EMP-coded tolerant lines ('EMP 385' and 'EMP 392') and the susceptible control 'BAT 41'. Thus, for these three genotypes, all subsequent hoppereburn symptoms are predictable by the type of feeding behavior performed on them. 'Porrillo Sintético' and 'EMP 84', considered borderline genotypes by the yield index, were overestimated and underestimated respectively, by the stylet penetration index. We postulate that, for these two genotypes, plant physiological responses to feeding (either compensatory or heightened sensitivity, respectively) synergize with type of feeding performed to generate the overall hopperburn condition. This multivariate analysis of electronic monitoring data was successfully used to devise an index of resistance. The implications of using the stylet penetration index and the advantages of using electronic monitoring in a bean-breeding program are discussed.     

Insulin Resistance Prevents AMPK-induced Tau Dephosphorylation through Akt-mediated Increase in AMPKSer-485 Phosphorylation

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, diabetes, and dyslipidemia, and insulin resistance (IR) is the central feature of MetS. Recent studies suggest that MetS is a risk factor for Alzheimer disease (AD). AMP-activated kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme and a key player in regulating energy metabolism. In this report, we examined the role of IR on the regulation of AMPK phosphorylation and AMPK-mediated Tau phosphorylation. We found that AMPK^Ser-485, but not AMPK^Thr-172, phosphorylation is increased in the cortex of db/db and high fat diet-fed obese mice, two mouse models of IR. In vitro, treatment of human cortical stem cell line (HK-5320) and primary mouse embryonic cortical neurons with the AMPK activator, 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), induced AMPK phosphorylation at both Thr-172 and Ser-485. AMPK activation also triggered Tau dephosphorylation. When IR was mimicked in vitro by chronically treating the cells with insulin, AICAR specifically induced AMPK^Ser-485, but not AMPK^Thr-172, hyperphosphorylation whereas AICAR-induced Tau dephosphorylation was inhibited. IR also resulted in the overactivation of Akt by AICAR treatment; however, preventing Akt overactivation during IR prevented AMPK^Ser-485 hyperphosphorylation and restored AMPK-mediated Tau dephosphorylation. Transfection of AMPK^S485A mutant caused similar results. Therefore, our results suggest the following mechanism for the adverse effect of IR on AD pathology: IR → chronic overactivation of Akt → AMPK^Ser-485 hyperphosphorylation → inhibition of AMPK-mediated Tau dephosphorylation. Together, our results show for the first time a possible contribution of IR-induced AMPK^Ser-485 phosphorylation to the increased risk of AD in obesity and diabetes.     

Correlations of cibarial muscle activities of Homalodisca spp. sharpshooters (Hemiptera: Cicadellidae) with EPG ingestion waveform and excretion

Fluid flow into and out of the stylets of xylem-ingesting sharpshooters (Hemiptera: Cicadellidae: Cicadellinae) is powered by muscles of the cibarial pump. Such fluid flow is crucial for transmission of Xylella fastidiosa, the Pierce’s Disease bacterium, yet has not been rigorously studied via electrical penetration graph (EPG) technology. We correlated EPG waveforms with electromyographically (EMG) recorded muscle potentials from the cibarial dilator muscles, which power the piston-like cibarial diaphragm. There was a 1:1 correspondence of each cycle of cibarial muscle contraction/relaxation with each plateau of EPG waveform C. Results definitively showed that the C waveform represents active ingestion, i.e. fluid flow is propelled by cibarial muscle contraction. Moreover, each C waveform episode represents muscular diaphragm uplift, probably combined with a “bounce” from cuticular elasticity, to provide the suction that pulls fluid into the stylets. Fine structure of the EPG ingestion waveform represents directionality of fluid flow, supporting the primary role of streaming potentials as the electrical origin of the C waveform. Rhythmic bouts of cibarial pumping were generally correlated with sustained production of excretory droplets. However, neither the onset nor cessation of ingestion was correlated with onset or cessation of excretion, respectively. Volume of excreta is an inexact measure of ingestion. Implications for using EPG to understand the mechanism of X. fastidiosa transmission are discussed.     

Morphology of Submerged Growth of Streptomycetes as a Taxonomic Aid: I. Morphological Development of Streptomyces aureofaciens in Agitated Liquid Media

In a study of the submerged growth morphology of 145 different streptomycetes in A C Broth, the species Streptomyces aureofaciens was observed to represent an unusual type. It was characterized by profuse mycelial segmentation, transformation of disarticulated fragments of segmented mycelium into chains of thickened arthrospores, and formation of filiform appendages on the arthrosporic cells giving an insectival appearance to these elements. This unusual morphology was determined to be a consistent feature in 110 strains of S. aureofaciens studied, hence suggesting a useful taxonomic aid in identification of this species. Preliminary studies of multiple strains of many different Streptomyces species indicate that other useful taxonomic features based on morphology of submerged growth are found in a significantly large part of the genus.